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Methods of Synthesizing a Prostacyclin Analog

Inactive Publication Date: 2015-11-05
CAYMAN CHEMICAL COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides methods that have higher yields and fewer byproducts than traditional methods. These methods use less toxic reagents and do not require additional chromatography for purification of intermediates. The intermediates generated by the present invention have improved e.e. and chemical purity. Additionally, the processes of the present invention are scalable to generate commercial quantities of the final compound.

Problems solved by technology

However, the methods of these teachings suffer from one or more problems including toxic oxidation reagents, reduced yields, elevated levels of impurities, poor scalability, and numerous chromatography steps to purify intermediates and final products.

Method used

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  • Methods of Synthesizing a Prostacyclin Analog
  • Methods of Synthesizing a Prostacyclin Analog
  • Methods of Synthesizing a Prostacyclin Analog

Examples

Experimental program
Comparison scheme
Effect test

example 1

(R)-oxiran-2-ylmethyl 3,5-dinitrobenzoate (1a)

[0419]

[0420]Triethylamine (8.52 g mL, 84.2 mmol, 1.25 equiv) and 4-dimethylaminopyridine (100 mg, 0.818 mmol, 0.01 equiv) were added to a solution of (S)-(−)-glycidol 1 (5.00 g, 67.5 mmol, 1.0 equiv, 99.5% ee) in anhydrous methylene chloride (100 mL) while stirring under nitrogen. The reaction was then warmed to 30° C. and 3,5-dinitrobenzoyl chloride (16.3 g, 70.9 mmol, 1.05 equiv) added drop-wise over 20 minutes as a solution in anhydrous methylene chloride (50 mL). After stirring at this temperature for 30 minutes, the reaction was quenched with addition of 10% aqueous potassium bicarbonate (50 mL) and cooled to room temperature while stirring for an additional 30 minutes. The two phases were separated and the organic phase washed with 10% aqueous citric acid (50 mL). The organic phase was then purified by filtration through a plug of silica gel giving 14.69 g of a white solid that was shown to be 99.4% e.e. by chiral HPLC. Recrystalli...

example 2

(S)-(−)-glycidol (1, ˜100% ee)

[0421]

[0422]A solution of dinitrobenzoate 1a (30.06 g, 112.1 mmol, 1.0 equiv) in anhydrous methanol (190 mL) was heated to reflux for 2 hours while stirring, under nitrogen. The reaction was then cooled to 0° C. in an ice bath causing formation of a crystalline solid that was removed by filtration and rinsed with ice cold methanol (15 mL). The filtrate was concentrated under reduced pressure resulting in formation of a white slurry that was dissolved in tert-butyl methyl ether (20 mL) and concentrated to dryness. The residue was again slurried in methanol (15 mL), the solid removed by filtration and rinsed with more methanol (5 mL). The filtrate was concentrated to give 7.6 g (92%) of the title compound as a pale yellow oil. Data for 1: Rf=0.12 (20% EtOAc / heptane).

example 3

(R)-tert-butyldimethyl(oxiran-2-ylmethoxy)silane (2a)

[0423]

[0424]To a 0° C. solution of tert-butyl(chloro)dimethylsilane (26.540 g, 176.21 mmol, 1.3 equiv) and imidazole (14.786 g, 217.19 mmol, 1.6 equiv) in dimethylformamide (80 mL) was added (S)-oxiran-2-yl methanol (10.013 g, 135.16 mmol, 1.0 equiv) drop-wise and the resulting mixture stirred at that temperature under nitrogen for 30 minutes. The reaction was then quenched with addition of saturated aqueous ammonium chloride (200 mL) and water (200 mL). The resulting mixture was extracted with heptane (5×200 mL) and the combined organic phases were washed with brine, dried (MgSO4) and concentrated to give 25.142 g (99%) of the title compound as a yellow oil. This material was used in the next step without purification. Data for 2a: Rf=0.64 (20% EtOAc / heptane); 1H NMR (400 MHz, CDCl3) δ 3.85 (dd, J=3.22, 12.01 Hz, 1H), 3.66 (dd, J=4.69, 12.01 Hz, 1H), 3.05-3.12 (m, 1H), 2.76 (dd, J=4.25, 5.13 Hz, 1H), 2.63 (dd, J=2.64, 4.98 Hz, 1H...

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Abstract

The present invention provides processes for preparing a prostacyclin analogue of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R10 is a linear or branched C1-6 alkyl. The processes of the present invention comprise steps that generate improved yields and fewer byproducts than traditional methods. The processes of the present invention employ reagents (e.g., the oxidizing reagent) that are less toxic that those used in the traditional methods (e.g., oxalyl chloride). Many of the processes of the present invention generate intermediates with improved e.e. and chemical purity; thereby eliminating the need of additional chromatography steps. And, the processes of the present invention are scalable to generate commercial quantities of the final compound.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This PCT application claims the benefit of U.S. provisional application Ser. Nos. 61 / 734,672, filed Dec. 7, 2012, and 61 / 777,882, filed on Mar. 12, 2013. Both of these documents are hereby incorporated by reference in their entireties.TECHNICAL FIELD OF THE INVENTION[0002]The present invention relates to processes and intermediates for the preparation of prostacyclin analog that are useful for treating hypertension and other diseases.BACKGROUND[0003]Prostacyclin derivatives and analogs are useful pharmaceutical compounds possessing activities such as platelet aggregation inhibition, gastric secretion reduction, lesion inhibition, vasodilation, and bronchodilation.[0004]Treprostinil is a synthetic prostacyclin derivative currently marketed as an active pharmaceutical ingredient (API) for its ability to inhibit pulmonary arterial hypertension under the trade name Remodulin®. Treprostinil was first described in U.S. Pat. No. 4,306,075.[0005]P...

Claims

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Application Information

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IPC IPC(8): C07C51/347C07D303/16C07D301/00C07C41/44C07C205/57C07C45/29C07F7/18C07D301/32
CPCC07C51/347C07F7/1856C07D303/16C07D301/32C07C41/44C07F7/1852C07C205/57C07C45/29C07D301/00C07F7/1804C07C41/26C07C51/09C07C51/412C07C2603/14C07D303/14C07D317/22A61P9/12C07C59/72C07C43/23
Inventor HERING, KIRK WILLAMCHAMBOURNIER, GILLESENDRES, GREGORY WILLIAMFEDIJ, VICTORKRELL, II, THOMAS JAMESMAHMOUD, HUSSEIN MAHMOUD
Owner CAYMAN CHEMICAL COMPANY
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